The presence of specific antibodies has been shown to play an important role in the protection against numerous human viral diseases. However, the role of the humoral immune response in HIV infection is still controversial. There are indications that the development of a broad neutralizing immune response, as found in long-term non-progressors, delays disease progression in contrast to rapid disease progressors where neutralizing antibody titers are often low. Other studies have suggested that mothers with high neutralizing antibody titers are less likely to transmit the virus to their newborns. A general correlation between the presence of neutralizing antibodies and disease manifestations was observed. Moreover, a decline in HIV specific antibody responses often predicts a poor diagnosis. Numerous animal and human trials were performed to study the role of antibodies in HIV-1 infection. Infusion of HIV-1 specific neutralizing antibodies to chimpanzees and macaques followed by an intravenous or mucosal challenge with HIV or chimeric simian/human immunodeficiency virus (SHIV) prevented infection or disease progression. Positive effects of passive immunization with monoclonal or polyclonal antibody preparations against HIV-1 were also observed in a number of trials in human volunteers. For example, the two human monoclonal antibodies 2F5 (ECACC Acc. Nr. 90091704) and 2G12 (ECACC Acc.Nr. 93091517) showed beneficial effects in a phase I clinical trial. Repeated infusions of both antibodies to HIV-positive patients resulted in reduction of viral loads and infected peripheral mononuclear cells (PBMC), increase of CD4+ T lymphocytes and complement activation.
So far, the number of monoclonal antibodies recognizing conserved epitopes and known to have a high therapeutic potential is low (D'Souza et al., J Infect Dis 1997; 175:1056-1062). Only the three monclonal antibodies (mAbs) 2F5, 2G12 (Buchacher et al., AIDS Res Hum Retroviruses 1994; 10:359-369), and IgG1b12 (Burton et al., Science 1994; 266:1024-1027) were reported to display significant cross-clade antiviral activity. The identification of monoclonal antibodies to conserved neutralizing B-cell epitopes on the HIV-1 envelope may not only be valuable for passive immunization strategies but also gives important information for a vaccine design based on the induction of a broad humoral immune response. There are indications that a vaccine based exclusively on T-cell epitopes would most probably not be sufficient to protect against HIV-1 infection (Parren et al., AIDS 1999; 13(suppl A):S137-S162).
Some years ago, we have established a panel of thirty-three human monoclonal antibodies against HIV-1 by immortalization of human peripheral blood lymphocytes from HIV-1 positive donors. Out of this panel two antibodies (2F5, 2G12) were identified to be potent inhibitors of laboratory and primary isolates of HIV-1. MAbs 2F5 and 2G12 were further developed and soon recognized to be two of the most potently neutralizing antibodies. Monoclonal antibody 4E10 (ECACC Acc. Nr. 90091703), originally an IgG3 antibody, was included into an evaluation program of the Antibody Serological Project (ASP) and was shown to neutralize some laboratory strains (D'Souza et al., AIDS 1994; 8:169-181).